Use of HCV‐infected organs in solid organ transplantation: An ethical challenge but plausible option

Due to the unfortunate epidemic of opioid overdose deaths among people who inject drugs (PWID) in North America, there has been an increase in the availability of hepatitis C (HCV)‐positive organs for transplantation and consequently the potential to decrease waiting times for solid organ transplantation if an HCV‐uninfected recipient is willing to accept an HCV‐positive donor. The confidence in this potential new strategy comes as a result of the advent of safe and highly effective pan‐genotypic direct‐acting antivirals (DAAs). This promising strategy has been the most widely studied in kidney transplantation. Liver transplantation has positive results preliminarily, but has even less available data because viable HCV‐infected donor livers are typically transplanted into HCV‐infected individuals. Further, while HCV‐infected heart and lung transplantation, which face additional post‐transplant issues, have shown encouraging results, these studies are small scale and are limited by short‐term follow‐up. Thus, it would be premature to implement this strategy as standard of care without large scale clinical and real‐world trials and longer‐term follow‐up studies. Further, the ethics of this practice need to be considered. While some transplant professionals argue that more harm will be done by not utilizing HCV‐infected organs, others contend that cautiously conducted multi‐centre studies involving extensive post‐transplant follow‐up are paramount prior to endorsing widespread implementation of this strategy. The ethical permissibility of this practice hinges on whether access to DAA therapy can be secured in advance, and prospective recipients understand and accept all the risks associated with acquiring HCV.     

Visualization of human gastric ancer with a novel indrared furescent labeling marker of anti‐carcinoembryonic antigen in vitro

Background : An indocyanine green (ICG) derivative (ICG N‐hydroxy sulfo succinimide ester (ICG‐sulfo‐OSu)) as an antibody labeling substance suitable for vital immunohistochemical staining, and an appropriate fluorescence imaging system for ICG‐sulfo‐OSu using infrared (IR) rays has been developed. The aim of this study is to demonstrate the antibody labeling substance at the cancerous tissue using this imaging system. Methods : ICG‐sulfo‐OSu‐labeled mouse antihuman carcinoembryonic antigen (CEA) monoclonal antibody and the imaging system for an IR fluorescent microscope were employed in this experiment. According to the standardized procedure, paraffin sections of 10 cases of gastric cancer were stained with anti‐CEA antibody by the avidin‐biotinylated peroxidase complex (ABC) method. Three cases of gastric cancer that stained positive were used for the IR imaging analysis. Results : The incubation of the gastric cancer specimens with ICG‐sulfo‐OSu‐anti‐CEA antibody‐complex resulted in positive staining in the lesion spots. Infrared fluorescence was observed in a well‐matched coincidence of oxidized 3,3′‐diamino‐benzidine tetrahydro‐chloride (DAB)‐positive sites. No chemical luminescence was confirmed in the rest of the neoplastic areas with ICG‐sulfo‐OSu complex. Conclusion : Specific antibodies with ICG‐sulfo‐OSu have a significant ability to label the cancer cells and reflect sufficient amounts of the fluorescence by IR rays. Therefore, ICG‐sulfo‐OSu is very useful for IR fluorescent endoscopic detection of microcancers by using the immunohistochemical staining method.     

Current challenges for men and women with mild‐to‐moderate haemophilia

Current treatments in the field of haemophilia are changing the phenotype of many patients with severe haemophilia to that of mild haemophilia. Despite this improvement, those with mild‐to‐moderate haemophilia A and haemophilia B continue to experience unmet needs. Whereas some patients with mild‐to‐moderate haemophilia experience similar complications to those of patients with severe haemophilia, they possess several unique attributes. These include a challenging diagnosis and variability in bleeding symptoms and treatment needs. In addition, haemophilia is an under‐recognized condition in women even though many women with mild‐to‐moderate haemophilia experience the same symptoms and complications as men with haemophilia. These women also have their own unique challenges with this disease. This supplement highlights many of the unmet needs in men and women with mild‐to‐moderate haemophilia. The conclusions of each of these papers reinforce the need for additional research and resources for this patient population.     

HMGCR‐associated myositis: a New Zealand case series and estimate of incidence

Statins are one of the most commonly prescribed drugs in New Zealand, with 525 772 or 16.5% of the adult New Zealand population prescribed a statin between June 2013 and July 2014. While generally well‐tolerated, statins are known to cause a range of muscle‐related side effects, ranging from myalgia to life‐threatening rhabdomyolysis. Recently, it has been recognised that in rare instances, statins can induce an immune‐mediated necrotising myositis with antibodies against 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR), the enzymatic target of statins. In 2014, anti‐HMGCR antibody testing was introduced to Canterbury Health Laboratories (CHL), with this being the only laboratory in New Zealand performing this test during the period of this case series. This article describes an index case and characterises the clinical features of a subsequent 12‐month series. From this series, we estimated the yearly incidence of HMGCR‐associated myositis at 1.7/million/year or ~1/90 000 New Zealand statin users.     

Harnessing Protocolized Adaptation in Dissemination: Successful Implementation and Sustainment of the Veterans Affairs Coordinated‐Transitional Care Program in a Non‐Veterans Affairs Hospital

The Department of Veterans Affairs (VA) Coordinated‐Transitional Care (C‐TraC) program is a low‐cost transitional care program that uses hospital‐based nurse case managers, inpatient team integration, and in‐depth posthospital telephone contacts to support high‐risk patients and their caregivers as they transition from hospital to community. The low‐cost, primarily telephone‐based C‐TraC program reduced 30‐day rehospitalizations by one‐third, leading to significant cost savings at one VA hospital. Non‐VA hospitals have expressed interest in launching C‐TraC, but non‐VA hospitals differ in important ways from VA hospitals, particularly in terms of context, culture, and resources. The objective of this project was to adapt C‐TraC to the specific context of one non‐VA setting using a modified Replicating Effective Programs (REP) implementation theory model and to test the feasibility of this protocolized implementation approach. The modified REP model uses a mentored phased‐based implementation with intensive preimplementation activities and harnesses key local stakeholders to adapt processes and goals to local context. Using this protocolized implementation approach, an adapted C‐TraC protocol was created and launched at the non‐VA hospital in July 2013. In its first 16 months, C‐TraC successfully enrolled 1,247 individuals with 3.2 full‐time nurse case managers, achieving good fidelity for core protocol steps. C‐TraC participants experienced a 30‐day rehospitalization rate of 10.8%, compared with 16.6% for a contemporary comparison group of similar individuals for whom C‐TraC was not available (n = 1,307) (P < .001). The new C‐TraC program continues in operation. Use of a modified REP model to guide protocolized adaptation to local context resulted in a C‐TraC program that was feasible and sustained in a real‐world non‐VA setting. A modified REP implementation framework may be an appropriate foundational step for other clinical programs seeking to harness protocolized adaptation in mentored dissemination activities.     

HIV co‐infection accelerates decay of humoral responses in spontaneous resolvers of HCV infection

Acute hepatitis C virus (HCV) infection is primarily followed by chronic infection, while spontaneous recovery of HCV infection (SR‐HCV) occurs in a minority of those infected. Identification of SR‐HCV clinically depends on two combined indicators, persistently undetectable peripheral HCV RNA and positivity for anti‐HCV. However, the characteristics of dynamic variation in anti‐HCV antibodies in SR‐HCV, especially in those patients co‐infected with HIV, are still undefined. In this study, a cohort of patients infected with HCV through commercial blood collection practices was studied. We found that the annual decreasing rate of anti‐HCV presented a gradually accelerated process in HCV resolvers. However, the variation in the decline of anti‐HCV presented a slowly accelerated process within the early decrease stage and a gradually decelerated process within the latter decrease stage. In addition, we deduced that it expended approximately 16 years from natural HCV recovery to undetectable peripheral anti‐HCV in HCV resolvers co‐infected with HIV, while this time was estimated to be 20 years in SR‐HCV without HIV co‐infection. Our data indicated that the decay of anti‐HCV was accelerated by HIV‐related impairment of immune function. The prevalence of HCV infection may be severely underestimated in this large‐scale retrospective epidemiologic investigation in an HIV‐infected population.     

Hereditary angioedema education in otolaryngology residencies: survey of program directors

Background

The objective of this work was to assess resident education regarding contemporary management of hereditary angioedema using a web‐based survey.

Methods

An 11‐item, multiple‐choice, electronic questionnaire was sent to all 106 accredited otolaryngology training programs in November 2016. Questions focused on resident education, management principles, and formalized assessment.

Results

A total of 34 program directors responded, representing 32% of otolaryngology residences. Ninety‐seven percent believed otolaryngology residents should be knowledgeable in the management of hereditary angioedema due to C1 inhibitor deficiency (C1‐INH‐HAE). Specifically, 38% and 26% of program directors felt their residents were comfortable and very comfortable in C1‐INH‐HAE management, respectively. Of those surveyed, 18% have educational simulation activities and a protocol in place for C1‐INH‐HAE management. Forty‐seven percent of respondents felt their training program provided adequate education and exposure to C1‐INH‐HAE. Over the last 5 years, 45% felt residents were exposed to 1 to 5 cases of C1‐INH‐HAE. Sixty‐seven percent of residents were trained in the management of C1‐INH‐HAE through in‐person lectures. Seventy‐one percent of programs had no formal assessment of resident competency in C1‐INH‐HAE management.

Conclusion

This study is the first to offer insight into C1‐INH‐HAE education and management principles in otolaryngology training programs. Surveyed program directors believe residents need a strong knowledge base in the management of C1‐INH‐HAE but less than half feel their trainees acquire the necessary exposure to this emergent disease process. Future research efforts in this area should aim to determine optimal educational activities as well as how to best incorporate this into otolaryngology residency curricula.

     

The protective effect of melatonin on methamphetamine‐induced calpain‐dependent death pathway in human neuroblastoma SH‐SY5Y cultured cells

Abstract: Methamphetamine (METH) is a potent psychostimulant drug that may cause neuronal cell degeneration. The underlying mechanisms of METH‐induced neuronal toxicity remains poorly understood. In this study, we investigated an important role of calpain‐dependent cascades in methamphetamine‐induced toxicity in human dopaminergic neuroblastoma SH‐SY5Y cultured cell lines. In addition, the protective effect of melatonin against METH‐induced calpain‐dependent death pathway was also investigated. The results of this study show that METH significantly decreased cell viability and tyrosine hydroxylase phosphorylation in SH‐SY5Y cultured cells. Melatonin reversed the toxic effect of METH by inducing cell viability. In addition, melatonin was able to restore the reduction in mitochondrial function and phosphorylation of tyrosine hydroxylase in SH‐SY5Y treated cells. An induction of calpain expression and activity but a reduction of calpain inhibitor (calpastatin) protein levels were observed in SH‐SY5Y cells treated with METH but these effects were diminished by melatonin. These results implicated calpain‐dependent death pathways in the processes of METH‐induced toxicity and also indicated that melatonin has the capacity to reverse this toxic effect in SH‐SY5Y cultured cells.     

Pembrolizumab in classical Hodgkin's lymphoma

Pembrolizumab is a humanized monoclonal antibody directed against programmed cell death protein 1 (PD‐1), a key immune‐inhibitory molecule expressed on T cells and implicated in CD4+ T‐cell exhaustion and tumor immune‐escape mechanisms. Classical Hodgkin's lymphoma (cHL) is a unique B‐cell malignancy in the sense that malignant Reed–Sternberg (RS) cells represent a small percentage of cells within an extensive immune cell infiltrate. PD‐1 ligands are upregulated on RS cells as a consequence of both chromosome 9p24.1 amplification and Epstein–Barr virus infection and by interacting with PD‐1 promote an immune‐suppressive effect. By augmenting antitumor immune response, pembrolizumab and nivolumab, another monoclonal antibody against PD‐1, have shown significant activity in patients with relapsed/refractory cHL as well as an acceptable toxicity profile with immune‐related adverse events that are generally manageable. In this review, we explore the rationale for targeting PD‐1 in cHL, review the clinical trial results supporting the use of checkpoint inhibitors in this disease, and present future directions for investigation in which this approach may be used.     

Establishment and characterization of a novel VEGF‐producing HHV‐8‐unrelated PEL‐like lymphoma cell line,OGU1

Primary effusion lymphoma (PEL) is a rare B‐cell lymphoma subtype that is characterized by lymphomatous effusion without the presence of masses, and it typically occurs in human immunodeficiency virus (HIV)‐infected individuals. Lymphoma cells are universally positive for human herpesvirus 8 (HHV‐8). Recently, a cavity‐based effusion lymphoma that is similar to PEL without HHV‐8 infection, called HHV‐8‐unrelated PEL‐like lymphoma, has been reported in non‐HIV‐infected individuals. However, the pathophysiology of this lymphoma is largely undefined. We established a novel B‐cell line OGU1 derived from a patient with HHV‐8‐unrelated PEL‐like lymphoma. Notably, OGU1 cells produced vascular endothelial growth factor (VEGF) and expressed VEGF receptor 1, whose inhibitors retarded cell growth. Because VEGF acts as a vascular permeability and growth factor, it could play a role, at least in part, in the pathogenesis of this unique lymphoma. Thus, the OGU1 cell line is useful for the investigation of HHV‐8‐unrelated PEL‐like lymphoma.     

QUANTITATIVE ANALYSIS OF LOW‐DOSE ASPIRIN‐ASSOCIATED SMALL BOWEL INJURY USING A CAPSULE ENDOSCOPY SCORING INDEX

Aim: The major limitation of capsule endoscopy (CE) has been the lack of a standardized and validated severity scale for mucosal injury. The aim of the present study was to verify the usefulness of quantifying small bowel mucosal changes associated with giving low‐dose aspirin (LDA) using a CE scoring index. Methods: The CE score for small bowel mucosal injury was investigated to evaluate the severity of mucosal injury. Healthy volunteers and patients suspected of having small bowel disease were recruited for this study. The short‐term LDA group (V + S‐LDA group) consisted of volunteers who took low‐dose aspirin for 14 days; this group was then compared with healthy volunteers who did not receive LDA treatment (V‐Control group). The long‐term LDA group (L‐LDA group) consisted of patients with at least a 3‐month history of daily LDA use; this group was compared with non‐users of LDA (P‐Control group). Results: The CE score was significantly higher in the V + S‐LDA group than in the V‐Control group. In the V‐Control group, almost all the subjects were categorized as exhibiting a ‘normal’ change. ‘Mild’ changes were observed significantly more frequently in the V + S‐LDA group than in the V‐Control group. The CE score was significantly higher in the L‐LDA group than in the P‐Control group. ‘Mild’ or ‘moderate or severe’ changes were observed significantly more frequently in the L‐LDA group than in the P‐Control group. Conclusion: The CE scoring system was useful for evaluating LDA‐associated small bowel mucosal disease activity and for objectively scoring the small bowel inflammatory disease state.     

Coronary obstruction following transcatheter aortic valve‐in‐valve implantation for failed surgical bioprostheses

Transcatheter aortic valve implantation (TAVI) for failed surgical bioprostheses, or “valve‐in‐valve” implantation, is a therapeutic option for high‐risk patients. While coronary occlusion during TAVI for native aortic stenosis has been described, in the setting of valve‐in‐valve implantation the bioprsthetic posts may be protective against this complication. We describe the first two cases of coronary occlusion following valve‐in‐valve therapy, both occurring during treatment of degenerated Mitroflow bioprostheses. Aortic root anatomy, coronary ostial position, and the specifics of the bioprosthetic valve type need to be considered in assessing and preventing this rare complication. © 2011 Wiley‐Liss, Inc.     

Accelerated orthotopic hepatocellular carcinomas growth is linked to increased expression of pro‐angiogenic and prometastatic factors in murine liver fibrosis

Background: Most experimental therapy studies are performed in mice that bear subcutaneous or orthotopic hepatoma but are otherwise healthy. We questioned whether a pre‐existing fibrosis affects tumour development of implanted syngenic hepatoma cells. To further investigate a selected panel of factors involved in tumour growth, tumour organ samples were characterized for gene expression of vascular endothelial growth factor (VEGF)‐A/‐C, VEGF receptors Flt1, Flk‐1, Flt‐4 and for VEGF‐A protein levels. Results: The presented data show that tumour sizes were 3.7‐fold increased and fibrotic livers had numerous satellites. Increased tumour sizes were associated with elevated intratumoral VEGF‐A protein amounts and intratumoral increased VEGF receptor gene expression levels in tumour tissue from fibrotic livers as compared with non‐fibrotic livers. Additionally, intratumoral gene expression levels of matrix metalloproteinase‐2 (MMP‐2) and MMP‐9 were elevated in fibrotic mice. Conclusion: Our results indicate that liver fibrosis stimulates tumour development of implanted syngenic hepatoma cells. Accelerated tumour growth was going along with elevated intratumoral VEGF‐A and VEGF‐A receptor status, which most probably mediated pro‐angiogenic and prometastatic effects in this model. Furthermore, advanced tumour spread was associated with increased MMP‐2/‐9 expression. These data suggest that the intratumoral VEGF‐A proteins levels and VEGF receptor status contribute to accelerated hepatocellular carcinoma development in fibrotic mice and that elevated MMP‐2, MMP‐9 and VEGF‐C levels could promote tumour metastasis in this model.     

Possibility of Decrease in CYP1A2 Function in Patients With End‐Stage Renal Disease

Propranolol, the substrate of cytochrome P450 (CYP) 1A2 and CYP2D6, has been reported to be in high concentrations in end‐stage renal disease (ESRD) patients. This has been thought to be due to the decrease in the nonrenal clearance of propranolol. The objective of this study is to elucidate the reason for the decrease in nonrenal clearance in ESRD patients. CYP1A2 and CYP2D6 activities were estimated by the phenacetin O‐deethylation and methoprolol O‐demethylation methods, respectively. Pooled normal serum and pooled uremic serum were deproteinized by methanol in order to exclude high‐molecular‐weight compounds. We selected as candidate inhibitors: uremic toxins such as 3‐indoxyl sulfate, 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoic acid, indole‐3‐acetic acid, and hippuric acid, and xanthine derivatives such as allantoin, uric acid, and xanthine. In this study, uremic serum was found to inhibit the CYP1A2‐mediated metabolism of phenacetin to acetaminophen in a concentration‐dependent and competitive manner. Xanthine also inhibited the metabolism of CYP1A2. On the other hand, uremic serum and the four uremic toxins did not inhibit the CYP2D6‐mediated metabolism of metoprolol to O‐demethylmetoprolol. In conclusion, this study suggests that the increase of the bioavailability of propranolol in ESRD is partly induced by the inhibition of the hepatic metabolism of CYP1A2 by xanthine in the uremic serum.     

High rate of hematological responses to sorafenib in FLT3‐ITD acute myeloid leukemia relapsed after allogeneic hematopoietic stem cell transplantation

Relapse represents the most significant cause of failure of allogeneic hematopoietic stem cell transplantation (HSCT) for FLT3‐ITD‐positive acute myeloid leukemia (AML), and available therapies are largely unsatisfactory. In this study, we retrospectively collected data on the off‐label use of the tyrosine kinase inhibitor sorafenib, either alone or in association with hypomethylating agents and adoptive immunotherapy, in 13 patients with post‐transplantation FLT3‐ITD‐positive AML relapses. Hematological response was documented in 12 of 13 patients (92%), and five of 13 (38%) achieved complete bone marrow remission. Treatment was overall manageable in the outpatient setting, although all patients experienced significant adverse events, especially severe cytopenias (requiring a donor stem cell boost in five patients) and typical hand‐foot syndrome. None of the patients developed graft‐vs.‐host disease following sorafenib alone, whereas this was frequently observed when this was given in association with donor T‐cell infusions. Six patients are alive and in remission at the last follow‐up, and four could be bridged to a second allogeneic HSCT, configuring a 65 ± 14% overall survival at 100 d from relapse. Taken together, our data suggest that sorafenib might represent a valid treatment option for patients with FLT3‐ITD‐positive post‐transplantation relapses, manageable also in combination with other therapeutic strategies.     

Body Composition Measurements from Birth through 5 Years: Challenges,Gaps, and Existing & Emerging Technologies—A National Institutes of Health workshop

Body composition estimates are widely used in clinical research and field studies as measures of energy‐nutrient balance, functionality and health. Despite their broad relevance and multiple applications, important gaps remain in techniques available for accurately and precisely quantifying body composition in infants and children from birth through 5 years. Identifying these gaps and highlighting research needs in this age group were the topics of a National Institutes of Health workshop held in Bethesda, MD, USA, 30–31 May 2019. Experts reviewed available methods (multicompartment models, air‐displacement plethysmography, dual‐energy X‐ray absorptiometry, weight‐length and height indices, bioimpedance analysis, anthropometry‐skinfold techniques, quantitative magnetic resonance, optical imaging, omics and D3‐creatine dilution), their limitations in this age range and high priority research needs. A summary of their individual and collective workshop deliberations is provided in this report.     

Development of a CENP‐A/CENP‐B–specific immune response in a patient with systemic sclerosis

Antibodies directed against an epitope motif on CENP‐A have been shown to cross‐react with mimotopes on other autoantigens and on Epstein‐Barr nuclear antigen 1 (EBNA‐1), suggesting a molecular mimicry. We describe here the gradual development of an anticentromere immune response in a patient with systemic sclerosis, which started from an antihistone response and was not mediated by molecular mimicry. Via an epitope on histone H3, the antibody response spread to a homologous epitope in the H3 homology domain of CENP‐A. This was followed by an intramolecular epitope spreading to N‐terminal peptides of CENP‐A containing the known epitope motif G‐P‐X₁‐R‐X₂. From there it spread to corresponding epitopes on CENP‐B and to mimotopes of the major CENP‐A epitope motif on other autoantigens including EBNA‐1. Whether the D‐penicillamine treatment received by this patient was involved in the triggering of this cascade remains a matter of speculation.     

EDTA‐induced pseudo‐neutropenia resolved with kanamycin

This report describes a case of spurious neutropenia caused by EDTA‐dependent in vitro agglutination of neutrophils. After raising the temperature of the sample to 37°C the agglutination was irreversible, but it resolved completely after addition of kanamycin. Previously this method has been shown to be effective in EDTA‐dependent pseudo‐thrombocytopenia, but this is the first report demonstrating successful application in EDTA‐dependent pseudo‐neutropenia.